MDR/XDR/PDR or DTR? Which definition best fits the resistance profile of Pseudomonas aeruginosa?

Purpose of review The aim of this narrative review is to compare the prognostic utility of the new definition of difficult-to-treat resistance (DTR) vs. established definitions in patients with Pseudomonas aeruginosa infection to understand the therapeutic implications of resistance classification and its impact on clinical outcome. Recent findings Among Gram-negative bacteria (GNB), P. aeruginosa (PA) is associated with high rates of morbidity and mortality, mostly related to its intrinsic capacity of developing antibiotic resistance. Several classifications of antibiotic resistance have been proposed in the last 15 years. The most common used is that from Magiorakos et al. including multidrug resistance (MDR), extensively drug-resistant (XDR) and pan drug resistance (PDR) according to the number of antibiotic classes showing in vitro activity. A further classification based on the resistance to specific antibiotic classes (i.e. fluoroquinolones, cephalosporins, carbapenem resistance) was also proposed. However, both of them have been criticized because of limited usefulness in clinical practice and for poor correlation with patient outcome, mainly in infections due to PA. More recently the new definition of difficult-to-treat resistance (DTR) has been proposed referring to nonsusceptibility to all first-line agents showing high-efficacy and low-toxicity (i.e. carbapenems, β-lactam-β-lactamase inhibitor combinations, and fluoroquinolones). Studies including large cohorts of patients with GNB bloodstream infections have confirmed the prognostic value of DTR classification and its clinical usefulness mainly in infections due to PA. Indeed, in the recent documents from the Infectious Diseases Society of America (IDSA) on the management of antibiotic resistant GNB infections, the DTR classification was applied to PA. Summary DTR definition seems to identify better than MDR/XDR/PDR and single class resistant categories the cases of PA with limited treatment options. It requires periodic revision in order to remain up-to-date with the introduction of new antibiotics and the evolving pattern of resistance.


INTRODUCTION
Pseudomonas aeruginosa (PA) has intrinsic resistance to many drug classes, the capacity to form biofilms and the ability to quickly acquire resistance upon exposure to antibiotics [1].The latest report of the European network EARS-Net showed that, in 2020, 30.1% of isolates were resistant to at least one antibiotic among carbapenems, fluoroquinolones, ceftazidime, piperacillin-tazobactam, and aminoglycoside.The highest percentage of resistance was observed for fluoroquinolones (19.6%), followed by piperacillin/ tazobactam (18.8%), carbapenems (17.8%), ceftazidime (15.5%) and aminoglycosides (9.4%) [2].
Multidrug resistance (MDR) definitions have changed over recent years.In a majority of studies, the classification adopted for antibiotic resistance was that proposed in 2008 by the US and European Centers for Disease Control and Prevention (CDC and ECDC) and published in 2012 by Magiorakos et al. [3].Multidrug -resistance (MDR) was defined as nonsusceptibility to !1 agent in !3 antimicrobial categories; extensively drug-resistant (XDR) as susceptibility limited to 2 categories; pan drug resistance (PDR), as nonsusceptibility to all agents in all antimicrobial categories [3].Despite their advantages for epidemiological studies, these definitions have some limitations; indeed, they weigh all antibiotics equally only considering their in vitro activity, regardless of their ''real-life'' effectiveness, pharmacokinetic/pharmacodynamic behaviors, and toxicity, limiting the bedside applicability of MDR and XDR categories.To fill this gap, in 2015 fluoroquinolone resistance (FQR), extended-spectrum cephalosporin resistance (ESCR), and carbapenem resistance (CR) definitions were introduced by CDC [4,5].Generally, in Enterobacterales and/or Acinetobacter baumannii infections, CR depicts cases with very limited treatment options.However, this could not be the case for PA where activity of FQ, ESC and/or b-lactam/b-lactamase inhibitor (BL/BLI) could be maintained also in presence of CR.
More recently, a new definition of resistance for Gram-negative infections has been proposed and labeled as difficult-to-treat resistance (DTR).This is based on the concept that nonsusceptibility to all first-line agents very often leads to use of secondline agents (such as aminoglycosides, tigecycline, or polymyxins) which are characterized by poorer pharmacokinetic properties and increased risk of toxicity, resulting in a better prediction of poor outcome.Validation on large patient cohorts has shown that this new definition is promising in better defining the correlation with clinical outcomes, and potentially in designing and evaluating clinical trials on the therapeutic management of antibiotic resistant Gram-negative infections [6].
Therefore, the aim of this narrative review is to examine and update available evidence about the prognostic utility of the new definition of DTR compared with the established definitions, in particular in patients with PA bloodstream infections (BSIs).

METHODS
We searched for randomized controlled trials (RCTs) and observational studies published from January 2022 to June 2023 on PUBMED using the following keywords ''difficult to treat resistance'' or ''difficult to treat definition'', ''Gram-negative bloodstream infection'', ''P.aeruginosa bloodstream infection''.Title and abstract screening were performed in order to check for consistency with the selected topic.Only studies published as full-text documents were reviewed.

KEY POINTS
The impact of new difficult-to-treat resistance (DTR) definition on evaluation of clinical outcome of patients with P. aeruginosa (PA)-infections is a key issue to consider in defining the burden of clinically meaningful co-resistance and its relationship to prognosis.
Magiorakos definitions have demonstrated some limits in showing consistent correlation with different patient outcomes.On the other hand, nonsusceptibility to all first-line and low-toxicity agents very often leads to clinically inappropriate empirical regimens and subsequent reliance on more unfavorable outcomes.
In some studies, DTR definition seemed to identify better than carbapenem resistance and multi-/extensive-/pandrug resistance categories the cases of P. aeruginosa with limited treatment options.
Certainly, since the introduction of new antibiotics, the concept of DTR is able to evolve over time to remain up-to-date and the assessment of what constitutes firstline agents will likely need to be revaluated., whereas DTR had a 20% higher adjusted mortality risk relative than CR (aRR, 1.2; 95% CI, 1.0-1.4;P ¼ 0.02), ESCR (1.2; 1.1-1.4;P ¼ .001),and FQR (1.2; 1.0-1.4;P ¼ 0.008) [7  && ].In our cohort of 1576 patients with GN-BSI, we [9] found that the most common causative microorganisms were E. coli 941 (59.7%),K. pneumoniae 326 (20.7%),Enterobacter spp.77 (4.9%), Proteus spp.55 (3.5%), P. aeruginosa 130 (8.2%), A. baumannii 33 (2.1%), S. maltophilia 14 (0.9%).The prevalence of DTR was 11% (n ¼ 174) and, whereas among K. pneumoniae and A. baumannii BSIs, CR and DTR rates were comparable, they differed in P. aeruginosa.Indeed, DTR seemed to identify better than CR and XDR categories the cases of P. aeruginosa with limited treatment options.At multivariate analysis, the independent risk factors for all-cause 30-day mortality were Charlson index, SOFA score, septic shock, CVC-related BSI, BSI due to carbapenemresistant Enterobacterales (CRE) or nonfermenting Gram-negative bacilli (NF-GNB), and complicated BSI.All the Magiorakos (MDR/XDR/PDR), CR, and DTR definitions were associated to a reduction of 30day survival.When the resistance definitions were incorporated into the baseline mortality model, they significantly improved discrimination of the multivariate model for predicting 30-day mortality; the net reclassification improvement was 9%, 10%, and 11% for DTR, MDR/XDR/PDR, and CR definitions, respectively.Probably, the CR category was shown to have the highest impact on predicting survival because of the high prevalence of CRE in our cohort and the low number of PA cases [9].
Similarly, Huh et al. [10] analyzed the impact of DTR on the 30-day mortality on a cohort of 1167 patients with GN-BSIs and compared DTR with traditional resistance classifications to determine their relative associations with clinical outcomes.The distribution of isolates was: E. coli 390 (33.4%),K. pneumoniae 292 (25%), P. aeruginosa 288 (24.7%), and A. baumannii 197 (16.9%).Overall, 147 (12.6%) were categorized as DTR, 17.7% of which were P. aeruginosa species.A multivariable model showed that only DTR, but not other categories, was significantly associated with mortality [adjusted odds ratio (aOR) 3.58, 95% CI 1.27-10.19].DTR was also a significant predictor for mortality in the analysis of propensity score-matched cohorts (aOR 3.48, 95% CI 1.82-6.79).It is worth mentioning that in this study the authors divided the resistance phenotypes into five hierarchical nonoverlapping categories: DTR; CR but not DTR (CRþ/DTRÀ); ESCR but not CR or DTR (ESCRþ/DTRÀ); FQR but not ESCR or CR (FQRþ/ESCR-CRÀ); and others.However, in real life resistance to multiple antibiotic classes can overlap (see Fig. 1).
To conclude, CR is generally associated with resistance to other high-efficacy, low-toxicity agents and therefore indirectly overlaps with DTR (see Fig. 1).However, when analyzed in very large cohorts, or when compared with CR episodes not exhibiting DTR, and/or in studies assessing only PA or with high PA prevalence [7 && ,10,11,12 && ] the DTR class was associated with an increased relative risk of mortality compared with other resistance definitions.For these reasons, we deem the definition of DTR adopted by Infectious Diseases Society of America (IDSA) [6] guidance documents is more appropriate than that of CR used by European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines [13] to address the best therapeutic options for PA.
Underlying mechanisms of resistance in difficult-to-treat resistance P. aeruginosa isolates and implications for therapeutic management Few data are available about the types and prevalence of main resistant mechanisms underlying DTR and CR phenotypes in PA isolates, and which antibiotics remain active against these strains.
In a nationwide Italian survey on 935 PA isolates obtained from patients with BSI and/or lower respiratory tract infections (LRTIs) in the period September 2013-November 2014, Giani et al. [15] investigated the antimicrobial susceptibility profiles to several old antibiotics and to ceftolozane/tazobactam (TOL), also depicting the molecular epidemiology of carbapenemase-producing isolates.TOL was the most active agent (90.9%) along with amikacin (88%) and colistin (84.7%).Meropenem was active against 65% of isolates.Overall, 85 strains (9.1%) were resistant to CTZ.Of these, 48 (5.1%) were carbapenemases producers.The most common carbapenemases were VIM-and IMP-types enzymes [15].Four (8.3%) carbapenemase producing strains were positive for a bla GES-5 gene.
Lasarte-Monterrubio et al. [17] evaluated the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam (these two last molecules are still not introduced in clinical practice) against a collection of 30 molecularly characterized ceftolozane/tazobactam and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously exposed to cephalosporins.The authors showed that cefiderocol, cefepime/taniborbactam, cefepime/zidebactam and imipenem/relebactam were able to overcome b-lactamasemediated ceftolozane/tazobactam and ceftazidime/ avibactam resistance in some PA strains.Among the isolates producing PDC, OXA-2 and OXA-10 variants conferring resistance to ceftolozane/tazobactam and ceftazidime/avibactam, cefiderocol was the most active agent, followed by imipenem/relebactam that was highly active against all isolates, except two carrying a VIM-20 carbapenemase.Cefepime/zidebactam and cefepime/taniborbactam displayed activity against, 83.3% and 73.3% of the strains evaluated, respectively.Resistance was observed in some strains with alteration of PBP3 or upregulation of mexAB-oprM or mexXY efflux pumps.
These studies confirm the high rate of in vitro activity for each of the new drugs recommended from IDSA guidelines for the treatment of DTR-PA infections [6].In addition, clinical studies have shown their good levels of effectiveness, safety and tolerability [18,19,20].Thus, probably the DTR classification for PA strains susceptible to such drugs could not be appropriate so far.On the other hand, these studies demonstrate that new resistance mechanisms to the new molecules are already emerging.Hence to maintain its usefulness, the DTR definition should be continuously updated referring to a resistance profile that can evolve according to the availability of new drugs and/or the emergence of new resistance mechanisms [7 && ].

CONCLUSION
In some studies, DTR definition seemed to identify better than CR and MDR/PDR/XDR categories those cases of P. aeruginosa infection with limited treatment options and highest risk of mortality.Probably because multidrug resistance per se is not associated with higher mortality when effective and safe antibiotics are used for definitive therapy [9,10].In addition, as emphasized in their manuscript by Kadri et al. [7 && ], ''DTR is not a fixed phenotype but rather a flexible framework'', therefore the concept of DTR needs to evolve over time to remain upto-date and the assessment of what constitutes firstline agents will likely need to be revaluated [21].

FIGURE 1 .
FIGURE 1. Schematic relationship of DTR with CDC-defined co-resistance phenotypes (adapted from Kadri SS et al.Difficult-totreat resistance in Gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents.Clin Infect Dis.Published online July 23, 2018.doi:10.1093/cid/ciy378).
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